Disassembly of interchromatin granule clusters alters the coordination of transcription and pre-mRNA splicing

To examine the involvement of interchromatin granule clusters (IGCs) in transcription and pre-mRNA splicing in mammalian cell nuclei, the serine-arginine (SR) protein kinase cdc2-like kinase (Clk)/STY was used as a tool to manipulate IGC integrity in vivo. Both immunofluorescence and transmission electron microscopy analyses of cells overexpressing Clk/STY indicate that IGC components are completely redistributed to a diffuse nuclear localization, leaving no residual structure. Conversely, overexpression of a catalytically inactive mutant, Clk/STY(K190R), causes retention of hypophosphorylated SR proteins in nuclear speckles. Our data suggest that the protein-protein interactions responsible for the clustering of interchromatin granules are disrupted when SR proteins are hyperphosphorylated and stabilized when SR proteins are hypophosphorylated. Interestingly, cells without intact IGCs continue to synthesize nascent transcripts. However, both the accumulation of splicing factors at sites of pre-mRNA synthesis as well as pre-mRNA splicing are dramatically reduced, demonstrating that IGC disassembly perturbs coordination between transcription and pre-mRNA splicing in mammalian cell nuclei

Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs

BACKGROUND: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip. RESULTS: We analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10(-7)) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03). CONCLUSIONS: We identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance

A Mindfulness Program Manual for People With Dementia

This article describes a 10-session group-based Mindfulness Program for people with mild to moderate dementia. It aims to equip people with dementia with skills to manage psychological distress, with support from carers. The Mindfulness Program was developed through reviews of existing literature, consultation with experts, and a focus group with people with dementia. In a randomized controlled feasibility and pilot trial with people with mild to moderate dementia in care homes, it was found to significantly increase quality of life. The manual presented here is designed to be administered flexibly to promote participants' personhood. The protocol is designed for use by therapists with experience in practicing mindfulness meditation

Memory with memory in genetic programming

We introduce Memory with Memory Genetic Programming (MwM-GP), where we use soft assignments and soft return operations. Instead of having the new value completely overwrite the old value of registers or memory, soft assignments combine such values. Similarly, in soft return operations the value of a function node is a blend between the result of a calculation and previously returned results. In extensive empirical tests, MwM-GP almost always does as well as traditional GP, while significantly outperforming it in several cases. MwM-GP also tends to be far more consistent than traditional GP. The data suggest that MwM-GP works by successively refining an approximate solution to the target problem and that it is much less likely to have truly ineffective code. MwM-GP can continue to improve over time, but it is less likely to get the sort of exact solution that one might find with traditional GP

Disruption of pre-mRNA splicing in vivo results in reorganization of splicing factors

We have examined the functional significance of the organization of pre-mRNA splicing factors in a speckled distribution in the mammalian cell nucleus. Upon microinjection into living cells of oligonucleotides or antibodies that inhibit pre-mRNA splicing in vitro, we observed major changes in the organization of splicing factors in vivo. Interchromatin granule clusters became uniform in shape, decreased in number, and increased in both size and content of splicing factors, as measured by immunofluorescence. These changes were transient and the organization of splicing factors returned to their normal distribution by 24 h following microinjection. Microinjection of these oligonucleotides or antibodies also resulted in a reduction of transcription in vivo, but the oligonucleotides did not inhibit transcription in vitro. Control oligonucleotides did not disrupt splicing or transcription in vivo. We propose that the reorganization of splicing factors we observed is the result of the inhibition of splicing in vivo

Development of the 'SNS Older Adults measure' (SNS-OA) to examine social network site use in older adults

Objectives: Social Networking Sites (SNSs) may ameliorate loneliness in later life but no measure of SNS use for this population exists. This study describes the development of the ‘SNS Older Adults measure’ (SNS-OA), to improve understanding of older adults’ SNS use and its relationship to social wellbeing. / Methods: The SNS-OA underwent initial development, including literature reviews and consultation with target population (n = 9) and experts (n = 9); piloting (n = 74), and evaluation of psychometric properties (n = 263). / Results: The final measure comprised three ‘motive’ scales (using SNSs to maintain close ties, maintain and strengthen weaker ties and diversion), and two ‘affect’ scales (positive/negative). Whilst many items were weakly endorsed by participants, the measure demonstrated good reliability (Cronbach α = 0.85; ICC = 0.82) and some convergent validity, with some subscales correlating with a personality measure in hypothesised directions. No statistically significant correlations were observed between the measure and social wellbeing. / Conclusions: Despite the measure’s limitations, this research has enabled a better understanding of SNS use in older adults and has important implications for research in this area. Findings also suggest a complex relationship between social wellbeing and SNS use in later life

Customs’ control on genetically modified food products across the border of the Eurasian Economic Union

Purpose: The purpose of the article is to determine the role of customs' control and directions of its improvement in the movement of genetically modified foods across the customs' border of the Eurasian Economic Union. In carrying out the study, the authors rely on the methods of theoretical modeling and interpretation of legal concepts and normative legal acts, which allowed to identify theoretical and applied problems of customs control in the conditions of Eurasian integration. Design/Methodology/Approach: The authors define the concepts of genetically modified foods and their turnover, highlight the problems of customs control over the movement of genetically modified foods across the customs border of the Eurasian Economic Union, and propose ways to improve it. Findings: The authors define the concepts of genetically modified foods and their turnover, highlight the problems of customs control over the movement of genetically modified foods across the customs border of the Eurasian Economic Union, and propose ways to improve it. Practical Implications: The results may be implicated into a legal framework of Russian Federation and improve customs' regulation both in Russia and abroad. Originality/Value: The main contribution of this article is the comprehensive analysis of legal and institutional background of genetically modified foods and their cross-border movement in EAEU countries as well as the measures of improving their customs' control.peer-reviewe

Too Good for Your Job? Disentangling the Relationships Between Objective Overqualification, Perceived Overqualification, and Job Dissatisfaction

In the present study, we investigated the relationships between objective overqualification, perceived overqualification, and job satisfaction based on the tenets of P-E fit theory, a commonly-used theoretical framework in the overqualification literature. Specifically, we tested whether employee perceptions of overqualification mediate the relationship between objective overqualification and job dissatisfaction. Results across two studies indicated that objective overqualification and job satisfaction independently predicted perceived overqualification, which contradicts the prevailing view in the literature of unidirectional effects between overqualification and strain outcomes. Study 1 used a cross-sectional survey of recent college graduates to test the overall mediation model. Although the model was supported, the relationship between objective overqualification and job satisfaction was not significant, raising the question of whether the hypothesized predictive relationship between perceived overqualification and job satisfaction is reversed. Study 2 tested directionality in the relationship between perceived overqualification and job satisfaction using a three-wave longitudinal panel design in a sample of full-time university staff employees. Results indicated that job dissatisfaction predicts subsequent perceived overqualification rather than the reverse

Control structural interaction testbed: A model for multiple flexible body verification

Conventional end-to-end ground tests for verification of control system performance become increasingly complicated with the development of large, multiple flexible body spacecraft structures. The expense of accurately reproducing the on-orbit dynamic environment and the attendant difficulties in reducing and accounting for ground test effects limits the value of these tests. TRW has developed a building block approach whereby a combination of analysis, simulation, and test has replaced end-to-end performance verification by ground test. Tests are performed at the component, subsystem, and system level on engineering testbeds. These tests are aimed at authenticating models to be used in end-to-end performance verification simulations: component and subassembly engineering tests and analyses establish models and critical parameters, unit level engineering and acceptance tests refine models, and subsystem level tests confirm the models' overall behavior. The Precision Control of Agile Spacecraft (PCAS) project has developed a control structural interaction testbed with a multibody flexible structure to investigate new methods of precision control. This testbed is a model for TRW's approach to verifying control system performance. This approach has several advantages: (1) no allocation for test measurement errors is required, increasing flight hardware design allocations; (2) the approach permits greater latitude in investigating off-nominal conditions and parametric sensitivities; and (3) the simulation approach is cost effective, because the investment is in understanding the root behavior of the flight hardware and not in the ground test equipment and environment

Decomposition of Unitary Matrices for Finding Quantum Circuits: Application to Molecular Hamiltonians

Constructing appropriate unitary matrix operators for new quantum algorithms and finding the minimum cost gate sequences for the implementation of these unitary operators is of fundamental importance in the field of quantum information and quantum computation. Evolution of quantum circuits faces two major challenges: complex and huge search space and the high costs of simulating quantum circuits on classical computers. Here, we use the group leaders optimization algorithm to decompose a given unitary matrix into a proper-minimum cost quantum gate sequence. We test the method on the known decompositions of Toffoli gate, the amplification step of the Grover search algorithm, the quantum Fourier transform, and the sender part of the quantum teleportation. Using this procedure, we present the circuit designs for the simulation of the unitary propagators of the Hamiltonians for the hydrogen and the water molecules. The approach is general and can be applied to generate the sequence of quantum gates for larger molecular systems